Distress and neuroticism as mediators of the effect of childhood and adulthood adversity on cognitive performance in the UK Biobank study

Childhood adversity and adulthood adversity affect cognition later in life. However, the mechanism through which adversity exerts these effects on cognition remains under-researched. We aimed to investigate if the effect of adversity on cognition was mediated by distress or neuroticism. The UK Biobank is a large, population-based, cohort study designed to investigate risk factors of cognitive health. Here, data were analysed using a cross-sectional design. Structural equation models were fitted to the data with childhood adversity or adulthood adversity as independent variables, distress and neuroticism as mediators and executive function and processing speed as latent dependent variables that were derived from the cognitive scores in the UK Biobank. Complete data were available for 64,051 participants in the childhood adversity model and 63,360 participants in the adulthood adversity model. Childhood adversity did not show a direct effect on processing speed. The effect of childhood adversity on executive function was partially mediated by distress and neuroticism. The effects of adulthood adversity on executive function and processing speed were both partially mediated by distress and neuroticism. In conclusion, distress and neuroticism mediated the deleterious effect of childhood and adulthood adversity on cognition and may provide a mechanism underlying the deleterious consequences of adversity.


Descriptive statistics
Models were run listwise including only subjects that had complete data for the model being tested.The structural equation model on childhood adversity included 64,051 participants aged 40 to 72 years (M = 55.63 years; SD = 7.61), 54.76% females.The structural equation model on adulthood adversity included 63,360 participants aged 40 to 72 years (M = 55.62 years; SD = 7.60), 54.66% females.A frequency table for childhood and adulthood adversity is displayed in Supplementary Table S2.

Exploratory factor analysis
The exploratory factor analysis showed that a two-dimensional factor structure describes the cognitive data in the UK Biobank best (Table 1 for factor loadings).Only two factors were retained because the eigenvalues associated with the remaining factors were negative 45 .The first factor comprised tasks measuring executive function including the Trail Making Test, the numeric memory test score, the fluid intelligence score, and the symbol digit test score.The second factor comprised a task measuring processing speed involving mean reaction time from the "snap game" and reaction time variability from the "snap game".A correlation analysis showed that the retained factors were weakly correlated (Pearson's r = − 0.278, p < 0.001).

Effects of childhood adversity on cognitive performance
Direct effects model A direct effects model (Fig. 1) with childhood adversity as the independent variable and executive function and processing speed as the latent, dependent variables had good model fit, CFI = 0.931, RMSEA = 0.049, and SRMR = 0.027.There was a moderate direct effect of childhood adversity on executive function (β = − 0.055, p < 0.001), but the direct effect of childhood adversity on processing speed was not significant (β = − 0.002, p = 0.621).

Indirect effects model
For the structural equation modelling (Fig. 2) with childhood adversity as the independent variable and executive function and processing speed as the latent, dependent variables, the model fit was very good 46,47 , CFI = 0.986, RMSEA = 0.028, and SRMR = 0.011.Higher levels of childhood adversity significantly predicted lower performance in tasks measuring executive function (β = − 0.037, p < 0.001), but did not predict performance in the www.nature.com/scientificreports/processing speed task (β = 0.003, p = 0.566).Higher levels of distress and neuroticism both predicted lower executive function (β = − 0.041, p < 0.001 and β = − 0.028, p < 0.001 respectively), and higher processing speed (β = 0.020, p = 0.001 and β = 0.018, p = 0.002 respectively).From this analysis the mediated paths of adversity on cognition were tested for significance.This analysis was followed by a post hoc mediation analysis to test if the effects of childhood adversity on executive function and processing were mediated by distress and/or neuroticism.
The effect of childhood adversity on executive function was partially mediated by distress (β = − 0.007, p < 0.001) and neuroticism (β = − 0.004, p < 0.001).16.5% of the effect of childhood adversity on executive function was mediated by distress (Indirect effect/Total effect Ratio = 0.165).10.4% of the effect of childhood adversity on executive function was mediated by neuroticism (Indirect effect/Total effect Ratio = 0.104).Significant complete mediation 48 or indirect-only mediation 49 was found for the effect of childhood adversity on processing speed with distress (β = 0.004, p = 0.001) and neuroticism (β = 0.003, p = 0.002) as mediators, thereby indicating that only the indirect path from childhood adversity to distress/neuroticism to processing speed was significant, whereas the direct path from childhood adversity to processing speed showed no effect.54.3% of the effect of childhood adversity on processing speed was mediated by distress (Indirect effect/Total effect Ratio = 0.543).48.5% of the effect of childhood adversity on processing speed was mediated by neuroticism (Indirect effect/ Total effect Ratio = 0.485).Table 2 shows the path coefficients and test statistics for the direct and indirect effects in the model as well as the components.

Effects of adulthood adversity on cognitive performance
Direct effects model A direct effects model (Fig. 3) with adulthood adversity as the independent variable and executive function and processing speed as the latent, dependent variables had good model fit, CFI = 0.930, RMSEA = 0.050, and SRMR = 0.027.There were moderate direct effects of adulthood adversity on executive function (β = − 0.119, p < 0.001) and processing speed (β = 0.040, p < 0.001).

Indirect effects model
For the SEM (Fig. 4) with adulthood adversity as the independent variable and executive function and processing speed as the latent, dependent variables, the model fit was very good 46,47 , CFI = 0.987, RMSEA = 0.028, and  www.nature.com/scientificreports/SRMR = 0.011.Higher levels of adulthood adversity significantly predicted lower performance in tasks measuring executive function (β = − 0.090, p < 0.001) and higher processing speed (β = 0.036, p < 0.001).Higher levels of distress and neuroticism both predicted executive function (β = − 0.033, p < 0.001 and β = − 0.025, p < 0.001 respectively) and higher processing speed (β = 0.015, p = 0.010 and β = 0.017, p = 0.003 respectively).From this analysis the significance of the mediated paths of adversity on cognition were tested for significance.The effect of adulthood adversity on executive function was partially mediated by distress (β = − 0.006, p < 0.001) and neuroticism (β = − 0.003, p < 0.001).6.6% of the effect of adult adversity on executive function was mediated by distress (Indirect effect/Total effect Ratio = 0.066).3.7% of the effect of adult adversity on executive function was mediated by neuroticism (Indirect effect/Total effect Ratio = 0.037).Similarly, the effect of adulthood adversity on processing speed was partially mediated by distress (β = 0.003, p = 0.011) and neuroticism (β = 0.002, p = 0.003).7.1% of the effect of adult adversity on processing speed was mediated by distress (Indirect effect/Total effect Ratio = 0.071).6% of the effect of adult adversity on processing speed was mediated by neuroticism (Indirect effect/Total effect = 0.060).Table 3 shows the path coefficients and test statistics for the direct and indirect effects in the model as well as the components.

Discussion
Here we have investigated whether the deleterious effect of childhood adversity and adulthood adversity on cognition was mediated by neuroticism or affect-related distress in the UK Biobank, a large cohort study.Childhood adversity showed a significant direct effect on executive function; however, childhood adversity did not show a direct effect on processing speed.By contrast, adult adversity showed significant direct effects on both executive function and processing speed.We found that the negative effect of childhood adversity on executive function was partially mediated by distress and neuroticism, whereas childhood adversity did not show a direct effect on processing speed.The effect of childhood adversity on processing speed was only apparent when considering the indirect path with neuroticism and distress as significant complete mediators.For adult adversity, our findings indicate that the detrimental effects of adult adversity on executive function and processing speed were partially mediated by distress and neuroticism.
Our findings are consistent with previous research that showed that adversity negatively affects cognitive performance in a variety of cognitive tasks 6,8,9,50   The findings from the exploratory factor analysis revealed two factors that are theoretically meaningful in the context of cognitive development and decline in adulthood.The factor "processing speed" can be linked to the processing-speed theory of adult age differences in cognition that suggest an association between increased age in adulthood and a decrease in the speed with which cognitive processes be executed 51 .Processing speed has been linked to brain integrity 52 and more specifically to white matter integrity 53 .In light of these theories, the effect of adversity on processing speed may reflect an accelerated aging process in response to the experience of adversity.Indeed, pervious research showed that child adversity was associated with accelerated aging 54 .The factor "executive function" can be linked to the prefrontal-executive theory that asserts that structural and functional changes in prefrontal cortex lead to declines in executive function, which in turn leads to lower cognitive performance 55,56 .prefrontal cortex is sensitive to stress and particularly vulnerable during development, which is the reason why early life adversity may impair development of the prefrontal cortex 57 .
Our study has several strengths: First, the study's sample size was large.Second, IRT was used to optimise the distress and neuroticism mediators.Compared to summated test scores, IRT has the advantage of improved precision and reliability through the identification and deletion of misfitting items 58 .Third, the analysis was adjusted for a range of covariates.
The present study has several limitations: Childhood adversity was assessed retrospectively self-report and might be subject to retrospective memory bias.Indeed, research indicated that high distress at recall was associated with a greater recall frequency of potentially traumatic events 59 .However, more recent research found that retrospectively reported child abuse was not biased by depression in adulthood 60 .Since we have found similar findings for the mediating role of distress and neuroticism for both childhood adversity and adulthood adversity on cognition, it may be unlikely that our findings are the result of a retrospective memory bias.
Another limitation resulting from the cross-sectional nature of the study design is that the mediators were acquired at approximately the same time as the independent and dependent variables in the mediation analysis model.Due to the implied causation of the mediation analysis, mediators should ideally be antecedents of the dependent variables and acquired before the dependent variables in a longitudinal design 61 .This was not possible in our analysis.However, the PHQ-9 from which our distress score was derived was previously found to be a proxy of lifetime depression 62 .Similarly, neuroticism remains rather stable in middle and older adulthood 63 .Thus, it seems to be reasonable to conclude that the distress score and neuroticism score from the UK Biobank may still serve as a proxy of past distress and neuroticism in mediation analysis.However, it should also be noted that the analysis does not shed light on the directionality of the association between distress/neuroticism and cognition and the association could be reversed.
Since we have seen here in a large and heterogenous cohort that the negative effect of adversities on cognition was mediated by neuroticism and mental-health related distress, this suggests that evidence-based interventions in clinical practice and policy-making can be specifically targeted at early mental health support.Interventions lowering mental-health-related distress or negative affectivity may have the potential to support cognitive health in individuals who experienced adversity in childhood or adulthood.Further experimental research investigating interventions for cognitive health is needed to confirm this implication.www.nature.com/scientificreports/Future research is required to investigate distress and neuroticism as mediators for the effect of adversity on cognition using a longitudinal design.Longitudinal designs have the advantage that (1) childhood adversity can be measured irrespective of any retrospective memory bias, (2) mediators in longitudinal designs are "true antecedents", (3) pre-/post-score comparisons on the dependent variables measuring cognitive health can reduce inter-individual variability in cognition.Future research should also investigate a broader range of mediators for the effect of adversity on cognition.
In conclusion, our study demonstrated that adulthood adversity negatively impacted both performances in executive function and processing speed.Distress and neuroticism mediated the detrimental effect of childhood and adulthood adversity on cognition.Childhood adversity only negatively affected executive function, whereas lower processing speed was only found when considering the indirect path with distress and neuroticism as mediators.

Design
Details of the design, participants, procedure and ethics of the UK Biobank study are available elsewhere 64 .The UK Biobank is a large, population-based study that involved the recruitment of 502,665 participants and the collection of comprehensive baseline data 64 .Ethical approval was granted to UK Biobank from the Research Ethics Committee-REC reference Ref 11/NW/0382 (approval letter dated 17th June 2011) 64 .All participants gave written informed consent prior to their participation.The UK Biobank study was conducted in accordance with the Declaration of Helsinki.

Materials
Adversity Separate adversity scores were used for childhood and adulthood adversity as previous research indicated differential effects of adversity on cognition across the lifespan 7 .The composite score for childhood adversity was derived from items from the Childhood Trauma Screener (CTS-5) 65 that were scored on a 5-point Likert scale: Never true (0), Rarely true (1), Sometimes true (2), Often (3), Very often true (4).The following items were used to yield the composite childhood adversity score: "When I was growing up… I felt that someone in my family hated me", "When I was growing up… People in my family hit me so hard that it left me with bruises or marks", "When I was growing up… Someone molested me (sexually)", and "When I was growing up… I felt loved".The composite score of childhood adversity was computed by summing up these four items and ranges from 0 to 16, with higher scores indicating higher levels of adversity.
The adulthood adversity score was derived from items that were adapted from the British Crime Survey 66 that were also scored on a 5-point Likert scale.The following items were used to yield the composite adulthood adversity score: "Since I was sixteen… A partner or ex-partner sexually interfered with me, or forced me to have sex against my wishes", "Since I was sixteen… A partner or ex-partner deliberately hit me or used violence in any other way", "Since I was sixteen… A partner or ex-partner repeatedly belittled me to the extent that I felt worthless", and "Since I was sixteen… I have been in a confiding relationship".The composite score of adulthood adversity was computed by summing up these four items.This composite score of adulthood adversity ranges from 0 to 16, with higher scores indicating higher levels of adversity.

Distress
The PHQ-ADS scale 21 was used to measure affect-related distress and an optimised latent trait variable was derived using item-response theory.The procedure used to derive the latent trait variable involved discarding misfitting items from the scale and applying an item-response theory model on 7 items with good model fit as previously described in more detail 67 .Data from three trials previously showed that the PHQ-ADS has high internal reliability and high construct and convergent validity 21 .

Neuroticism
The Eysenck Personality Questionnaire 68 was used to measure neuroticism and an optimised ed latent trait variable was derived following a procedure previously described 69 .
Cognition Details of the cognitive tasks selected for this study are reported in the supplementary materials.In brief, we used the digit span task assessing numeric short-term memory, the fluid intelligence test, symbol matches task measuring complex attention, and trail-making tasks that measure executive function, visual scanning, and working memory as well as the average and variability of reaction times in the snap game task.

Covariates
Models were adjusted for age, gender, Townsend deprivation index (TDI) and education (see supplementary materials, methods section for details).

Analytic strategy
UK Biobank data for this analysis (application 15697) were uploaded onto the Dementias Platform UK (DPUK) Data Portal 70 and analysed using STATA SE 17.0 71 .An SEM was fitted to the data with childhood adversity or adulthood adversity as the independent variable, cognitive performance as the dependent variable and distress and neuroticism as mediators.The Stata package medsem 72 was used to test for mediational hypotheses 48,49

Figure 2 .
Figure 2. Path diagram showing the relationship between variables entered in the structural equation modelling with childhood adversity as the independent variable, executive function and processing speed as latent dependent variables and distress and neuroticism as mediators.Note: Path-coefficients are standardized coefficients.Covariates not shown for display purposes.Covariates include sex, age, Townsend deprivation index, and education.*p < 0.05, **p < 0.01, ***p < 0.001.

Figure 4 .
Figure 4. Path diagram showing the relationship between variables entered in the structural equation modelling with adulthood adversity as the independent variable, executive function and processing speed as latent dependent variables and distress and neuroticism as mediators.Note: Path-coefficients are standardized coefficients.Covariates not shown for display purposes.Covariates include sex, age, Townsend deprivation index, and education.*p < 0.05, **p < 0.01, ***p < 0.001.

Table 1 .
Exploratory factor analysis with an orthogonal varimax rotation on cognitive scores in the UK Biobank.N = 64,051.Factor loadings > 0.3 are shown in bold.Only factors with positive eigenvalues were retained, yielding a two-factor solution.TMT trail making test, RT reaction time.

Table 2 .
Path analysis showing the effects of childhood adversity on cognitive performance and mediation by distress and neuroticism.Results are adjusted for covariates (sex, age, Townsend deprivation index, years of education).β Standardized path coefficient, SE standard error, CI confidence interval, LL lower limit, UL upper limit.a Partial mediation.b Complete (in-direct only) mediation.

Table 3 .
Path analysis showing the effects of adult adversity on cognitive performance and mediation by distress and neuroticism.Results are adjusted for covariates (sex, age, Townsend deprivation index, years of education).β standardized path coefficient, SE standard error, CI confidence interval, LL lower limit, UL upper limit.a Partial mediation.b Complete mediation.